The prefrontal cortex (PFC) has emerged as one of the regions most consistently impaired in major depressive disorder (MDD). Although functional and structural PFC abnormalities have been reported in both individuals with current MDD as well as those at increased vulnerability to MDD, this information has not translated into better treatment and prevention strategies. Here, we argue that dissecting depressive phenotypes into biologically more tractable dimensions – negative processing biases, anhedonia, despair-like behavior (learned helplessness) – affords unique opportunities for integrating clinical findings with mechanistic evidence emerging from preclinical models relevant to depression, and thereby promises to improve our understanding of MDD. To this end, we review and integrate clinical and preclinical literature pertinent to these core phenotypes, while emphasizing a systems-level approach, treatment effects, and whether specific PFC abnormalities are causes or consequences of MDD. In addition, we discuss several key issues linked to cross-species translation, including functional brain homology across species, the importance of dissecting neural pathways underlying specific functional domains that can be fruitfully probed across species, and the experimental approaches that best ensure translatability. Future directions and clinical implications of this burgeoning literature are discussed.

前额叶皮层 (PFC) 已成为重度抑郁症 (MDD) 中受损最严重的区域之一。尽管功能性和结构性 PFC 异常在患有当前 MDD 的个体以及易患 MDD 的个体中均有报道，但这些信息并未转化为更好的治疗和预防策略。在这里，我们认为将抑郁表型分解为生物学上更容易处理的维度——消极处理偏差、快感缺乏、绝望样行为（习得性无助）——提供了独特的机会，可以将临床发现与抑郁症相关临床前模型中出现的机制证据相结合，从而有望以提高我们对 MDD 的理解。为此，我们回顾并整合了与这些核心表型相关的临床和临床前文献，同时强调系统级方法、治疗效果以及特定 PFC 异常是 MDD 的原因还是后果。此外，我们讨论了与跨物种翻译相关的几个关键问题，包括跨物种的功能性大脑同源性、剖析特定功能域下的神经通路的重要性，这些神经通路可以跨物种进行富有成效的探索，以及最能确保可译性的实验方法。讨论了这些新兴文献的未来方向和临床意义。我们讨论了与跨物种翻译相关的几个关键问题，包括跨物种的功能性大脑同源性、剖析特定功能域下的神经通路的重要性，这些神经通路可以跨物种进行富有成效的探索，以及最能确保可翻译性的实验方法。讨论了这些新兴文献的未来方向和临床意义。我们讨论了与跨物种翻译相关的几个关键问题，包括跨物种的功能性大脑同源性、剖析特定功能域下的神经通路的重要性，这些神经通路可以跨物种进行富有成效的探索，以及最能确保可翻译性的实验方法。讨论了这些新兴文献的未来方向和临床意义。